1. Field Of The Invention
This invention relates to a unique total synthesis for preparing dl biotin which starts with methoxycyclohexane and utilizes the basic concept of forming a furoxan system to construct the biotin nucleus. Within the total synthesis of biotin are several unique individual steps heretofore unknown in the prior art, as well as several unique intermediates which are formed in the process for making biotin.
2. Prior Art
Biotin is one of the water soluble vitamins which is a monocarboxylic acid containing a cyclic urea structure with a sulfur in a thioether linkage as shown in FIG. 1 below ##STR1## Biotin contains 3 asymmetric carbons (circled, above) and therefore there can exist as 4 racemates or 8 stereo isomers of the biotin structure. As a member of the vitamin B family biotin has, for a long time, been also known as the essential factor in the processes and maintenance of normal metabolism. Biotin's roles are discussed in an article entitled "Biotin-A Ubiquitous And Versatile Vitamin" by Dr. J. C. Bauernfeind, Feed Stuffs, 41, 32-34, 1969.
Several processes are known for preparing biotin and these are discussed in Comprehensive Biochemistry, 11, 66-81, Chapter VI entitled "Biotin" by L. H. Sternbach. As pointed out in that discussion, biotin was first synthesized by Harris and co-workers in the early 40's by forming a thiophene intermediate and eventually forming the keto 3,4 imidazolido group as the last step. A second route started with thiophane and proceeded through a series of reactions finally forming the 3,4 imidazolido group at the end of the reaction. A third synthesis also started with a substituted thiophane and progressed in a way similar to the second synthesis, however at each step meticulous care was taken to establish the steric configuration of the substituents in positions 3 and 4.
The commercial synthesis of biotin was developed by Hoffman La Roche and differs from the first three syntheses in several respects, i.a. that the imidazolidone ring is formed first with the 2 constituents (carbonyls) cis to each other.
The process for the synthesis of biotin according to this invention is a complete departure from anything taught in the prior art and involves starting with an alkoxy cyclohexene and proceeding through various steps to form a novel thieno furoxan structure and novel thiophenes to ultimately form biotin.